Template:Modafinil/Pharmacology
Pharmacology
Although the exact mechanisms by which modafinil and its R-enantiomer, armodafinil, decrease sleepiness are not fully understood, evidence suggests that these agents promote wakefulness by acting directly or indirectly on many components of the sleep / wake circuit. Modafinil and armodafinil are hypothesized to inhibit GABA and promote dopamine, norepinephrine, histamine, and hypocretin / orexin.[1][2][3][4]
Modafinil and its R-enantiomer, armodafinil, increase both norepinephrine (NE) and dopamine (DA), possibly via their blockade of both the NE and DA reuptake transporters (NET and DAT, respectively). The actions of NE at alpha-adrenergic receptors and DA at dopamine D2 receptors are thought to contribute to the wake-promoting properties of modafinil. Orexin is a key component of the arousal system; thus, the hypothesized action of modafinil on the orexinergic system may help increase alertness. Additionally, modafinil may indirectly increase histamine, either by reducing GABAergic inhibition of histaminergic neurons or via actions at orexinergic neurons. The increase in histamine may contribute to both the wake-promoting effects of modafinil as well as the potential of modafinil to increase alertness.[1][3][5]
In genetically engineered mice lacking the dopamine transporter (DAT), modafinil lacked wake-promoting activity, suggesting that this activity was DAT-dependent. However, the wake-promoting effects of modafinil, unlike those of amphetamine, were not reduced by the dopamine receptor antagonist haloperidol in rats. In addition, alpha-methyl-p-tyrosine, an inhibitor of dopamine synthesis, blocks the action of amphetamine but does not block locomotor activity induced by modafinil.
- ↑ 1.0 1.1 Morrissette, D. A. (December 2013). "Twisting the night away: a review of the neurobiology, genetics, diagnosis, and treatment of shift work disorder". CNS Spectrums. 18 (s1): 42–54. doi:10.1017/S109285291300076X. ISSN 1092-8529.
- ↑ Touitou, Y., Bogdan, A. (February 2007). "Promoting adjustment of the sleep–wake cycle by chronobiotics". Physiology & Behavior. 90 (2–3): 294–300. doi:10.1016/j.physbeh.2006.09.001. ISSN 0031-9384.
- ↑ 3.0 3.1 Darwish, M., Kirby, M., D’Andrea, D. M., Yang, R., Hellriegel, E. T., Robertson, P. (November 2010). "Pharmacokinetics of armodafinil and modafinil after single and multiple doses in patients with excessive sleepiness associated with treated obstructive sleep apnea: A randomized, open-label, crossover study". Clinical Therapeutics. 32 (12): 2074–2087. doi:10.1016/j.clinthera.2010.11.009. ISSN 0149-2918.
- ↑ Erman, M. K., Yang, R., Seiden, D. J. (2012). "The effect of armodafinil on patient-reported functioning and quality of life in patients with excessive sleepiness associated with shift work disorder: a randomized, double-blind, placebo-controlled trial". The primary care companion for CNS disorders. 14 (4): PCC.12m01345. doi:10.4088/PCC.12m01345. ISSN 2155-7772.
- ↑ He, B., Peng, H., Zhao, Y., Zhou, H., Zhao, Z. (December 2011). "Modafinil treatment prevents REM sleep deprivation-induced brain function impairment by increasing MMP-9 expression". Brain Research. 1426: 38–42. doi:10.1016/j.brainres.2011.09.002. ISSN 0006-8993.